Understanding individual differences in pain and analgesic responses has tremendous scientific and clinical implications. Evidence from both human and non-human species indicates robust inter-individual variability in basal nociceptive sensitivity and in responses to opioid analgesics. Increasing evidence suggests that genetic factors contribute to individual differences in pain perception and analgesic responses. Over the past decade, a burgeoning rodent literature has demonstrated genetic influences on nociceptive and antinociceptive responses. Limited research regarding genetic influences on pain and analgesia is available in humans; although, 2 recent studies have reported associations between specific single nucleotide polymorphisms (SNPs) and experimental pain responses. Interestingly, multiple pain-related genetic associations identified in rodents and in humans have been sex-dependent. Therefore, we propose the following translational approach to investigating genetic influences on pain and analgesia, and the sex-dependence thereof. First, recent and emerging findings from quantitative trait locus (QTL) mapping in mice (from Dr. Mogil's lab) will identify candidate genes that influence variability in nociceptive and analgesic sensitivity. Second, the association of these candidate genes to pain sensitivity and analgesic responses in humans will be determined using sophisticated, clinically relevant psychophysical procedures. Third, pharmacologic and molecular approaches will be used to elucidate the mechanisms underlying the newly discovered sex-related genetic association to pain and/or opioid analgesia. Specifically, based on our preliminary results in both mice and humans, we plan to: 1) characterize associations of the melanocortin-1 receptor gene (MC1R) to basal pain sensitivity and opioid analgesia and to determine the sex-dependence of these associations; and 2) characterize the association of the u-opioid receptor gene (OPRM1), the 6-opioid receptor gene (OPRD1), and the K-opioid receptor gene (OPRK1) to basal pain sensitivity and opioid analgesic responses. We have implemented this translational approach successfully in the past, and we believe that this model of interdisciplinary research represents the ideal pathway for gene discovery and ultimately for translation to the clinical setting.